Essential Thrombocythemia

Essential Thrombocythemia

Essential Thrombocythemia Guido Finazzia and Claire Harrisonb Significant progress in our understanding of the molecular pathogenesis of essential thr...

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Essential Thrombocythemia Guido Finazzia and Claire Harrisonb Significant progress in our understanding of the molecular pathogenesis of essential thrombocythemia (ET) and the other Philadelphia (Ph) chromosome–negative myeloproliferative disorders (MPDs) has recently been achieved. Unfortunately, the diagnosis of ET still relies on a set of exclusion criteria developed years ago, as recent advances have yet to be evaluated for this purpose. The clinical course of ET is characterized by an increased incidence of thrombotic and hemorrhagic complications and an inherent tendency to progress into myelofibrosis or acute myeloid leukemia (AML). There is concern about undesirable effects of cytoreductive therapy given to prevent vascular events, particularly the risk of accelerating the rate of hematologic transformation. Thus, management involves modification of reversible vascular risk factors and further stratification according to the thrombotic risk. Myelosuppressive agents are not recommended in low-risk patients, whereas controlled studies support the therapeutic value of hydroxyurea (HU) plus aspirin in high-risk cases. Anagrelide or interferon-alpha (IFN-␣) could be considered as second-line therapy in patients refractory or intolerant of HU. IFN-␣ is preferred in pregnant women. Semin Hematol 42:230-238 © 2005 Elsevier Inc. All rights reserved.


ssential thrombocythemia (ET) is currently classified as a myeloproliferative disorder (MPD), which is a heterogeneous category of clonal stem cell diseases that also includes polycythemia vera (PV), myelofibrosis with myeloid metaplasia (MMM), and chronic myeloid leukemia (CML). Among the MPDs, ET shows longer median survival as well as lower transformation rates into either acute leukemia (AL) or MMM when compared to either PV or MMM. However, the clinical course of ET is complicated by thrombotic and hemorrhagic episodes that occur more frequently in older patients and those with previous vascular events. There is an ongoing debate as to whether the evolution to MMM or AL is part of the natural history of the disease or is related to the use of cytoreductive agents given to control the myeloproliferation and avoid vascular complications. But it is most likely that factors intrinsic to ET as well as cytoreductive therapy combine to affect transformation to MMM or AL. Hence, the best strategy is to limit the cytotoxic therapy to patients stratified on the basis of their risk for developing vascular events. Thus, the crucial point in the evaluation of a patient with ET is careful ongoing assessment of the thrombotic risk to establish the appropriate management. This chapter reviews the


of Hematology, Ospedali Riuniti, Bergamo, Italy.

bDepartment of Hematology, Guy’s and St. Thomas’ NHS Foundation Trust,

London, UK. Address correspondence to Guido Finazzi, Senior Consultant, Hematology, Ospedali Riuniti, Largo Barozzi 1, 24128 Bergamo, Italy. E-mail: [email protected]


0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.05.022

molecular basis, diagnostic criteria, natural history, and riskadapted therapy of ET and includes some recommendations for the management of pregnancy.

Molecular Pathogenesis ET is thought to result from transformation of a multipotent hematopoietic progenitor. This concept was originally proposed by Fialkow et al, who demonstrated a clonal pattern of X inactivation in multiple myeloid lineages but not in lymphoid cells.1 However, subsequent studies in ET have now demonstrated that a significant proportion, up to 50%, of patients do not appear to have clonal hematopoiesis,2-5 an observation that may also reflect the limited ability of current techniques to detect a small proportion of clonally derived cells. Recently, a number of biologic features of interest in PV, including polycythemia rubra vera-1 (PRV-1), a member of the uPAR receptor superfamily, erythropoietin levels, and spontaneous erythroid colonies, have been investigated in ET. Up to 50% of ET patients have increased levels of PRV-1 mRNA in granulocytes.6 Those ET patients with normal PRV-1 expression and no detectable spontaneous erythroid colonies are more likely to have polyclonal hematopoiesis.7,8 Furthermore, a subgroup of ET patients (up to 30%) have reduced erythropoietin levels and a possible increased risk of thrombotic events.9 Clonality and serum erythropoietin levels are reported to be independent of each other.10 The identification of thrombopoietin (TPO) triggered intensive evaluation of the cytokine and its receptor c-Mpl in

Essential thrombocytopenia patients with ET. This has generally proven puzzling and disappointing. TPO levels are paradoxically elevated in ET, other MPDs, and reactive thrombocytosis,11,12 but an explanation for this rise has yet to be found. In some familial but not acquired thrombocytoses, well-described gain of function mutations occur within the 5=UTR of the TPO gene, causing elevated TPO levels.13-18 Reduced megakaryocyte and platelet expression of c-Mpl was found in some patients with ET12,19,20 but also in patients with familial ET caused by a TPO gene mutation.8 A mutation in c-Mpl has been identified in one family with congenital thrombocytosis,21 but no mutations have been identified in sporadic or acquired ET. Hematopoietic progenitors derived from many patients with ET may be hypersensitive to cytokines such as thrombopoietin or erythropoietin.22-24 This has drawn attention to downstream receptor events. Several groups concurrently detected an acquired mutation of JAK2 in a majority of patients with PV, as well as approximately half of those with ET or MMM.25-28 The mutation is located within the negative regulatory pseudo kinase domain, also called Janus homology 2 (JH2) domain, and replaces valine within position 617 (V617F) of the Jak2 protein (see Kralovics et al in this issue). This finding is largely consistent with the hypersensitivity to growth factors in serum-free media.

Diagnostic Criteria There is no single clinical or laboratory finding that permits a positive diagnosis of ET. Thus, the diagnosis must be mainly reached by excluding other myeloproliferative or myelodysplastic disorders (MDS) or the conditions associated with a reactive thrombocytosis. This principle was used in the diagnostic criteria developed by the Polycythemia Vera Study Group (PVSG)29 (Table 1) and the World Health Organization (WHO)30 (Table 2).

Platelet Count The current criteria for ET include a persistent platelet count of greater than 600 ⫻ 109/L. However, it has been suggested that the platelet count criterion should be reduced to greater than 400 ⫻ 109/L since, in long-term follow-up studies, the clinical course of patients with platelet counts between 400 and 600 ⫻ 109/L was found to be indistinguishable from that of patients with a clear diagnosis of ET.31,32 The major problem with this approach is that lowering the platelet count threshold will improve the sensitivity but reduce the specificity of ET diagnosis. Therefore, the selection of a cut-off of 600 ⫻ 109/L is probably the most appropriate for the selection of ET patients to be included in therapeutic trials. In clinical practice, a lower platelet count can be considered for an initial screening but should be supported by other clinical and laboratory ET features.

231 ET from reactive thrombocytosis and other MPDs have been proposed. It has been suggested that ET can be positively diagnosed by careful, quantitative examination of the bone marrow biopsy33; this forms the basis of a positive marker for ET in the WHO diagnostic criteria.30 Typical clustering of enlarged megakaryocytes with multilobated nuclei has been advocated to represent the hallmark feature of the disease. The background of hematopoiesis in ET is characterized by a discrete pattern of minimal or no hyperplastic erythropoiesis, no change in granulopoiesis, almost no fibrosis, and reduction of stainable iron. A detailed evaluation of bone marrow features may also help to distinguish “true” ET from the initial stages of MMM, PV, or myelodysplasia. “Early” myelofibrosis is characterized by increasing cellularity with prominent neutrophil granulopoiesis, borderline to slight reticulin fibrosis, and pronounced abnormalities of megakaryocyte differentiation, including hyperchromasia and marked nuclear-cytoplasmatic deviation. Notably, patients with these morphologic features frequently develop an overt myelofibrosis and have a significantly worse life expectancy. However, an experienced observer and a well-standardized procedure are required to diagnose ET by examination of the bone marrow biopsy. This is one of the major limitations of the diagnostic classifications of ET based on bone marrow histology. Furthermore, the reliability of bone marrow histology for the diagnosis of ET has not been evaluated prospectively. Some authors have shown that endogenous erythroid colonies or culture examining megakaryocyte colony-forming unit (CFU-Mk) growth may be reliable markers of the disease.22,34 However, these investigations are not widely available and they are expensive and technically demanding, and therefore may be suitable only for research purposes in occasional patients but not for general use. Such colonies have been reported in patients with a reactive thrombocytosis.32 Nonstimulated metaphases obtained from marrow aspirates should be examined for cytogenetic abnormalities. This is primarily important to exclude the presence of the Philadelphia (Ph) chromosome, the genotypic hallmark of CML. Karyotypic abnormalities generally arise upon transformation of ET to AL when deletions or elongations of the short arm of chromosomes 1, 2, 5, 17, 20, and 21 are the most frequent defects.35 In summary, positive assays for establishing the presence of ET are promising but still insufficiently standardized to be recommended for diagnostic use in all patients. Despite current limitations, this is an expanding field and it is likely that in due course these tests will complement or substitute the time-honored PVSG criteria or validate those of the WHO.

Epidemiology and Clinical Course Frequency

Positive Criteria for Diagnosing ET The approach to ET as a diagnosis of exclusion is intrinsically unsatisfactory, and positive criteria that would distinguish

According to population-based epidemiologic studies,36,37 the incidence rates of ET range from 15 to 25 cases per million inhabitants annually. These figures are in agreement

G. Finazzi and C. Harrison

232 Table 1 PVSG Updated Diagnostic Criteria for Essential Thrombocythemia I II III IV V


Platelet count >600,000/␮L Hematocrit <51% for males or <48% for females or normal red blood cell mass (males <36 mL/kg, females < 32 mL/kg) Stainable iron in marrow or normal serum ferritin or normal red blood cell mean corpuscular volume* No Philadelphia chromosome or bcr/abl gene rearrangement Collagen fibrosis of marrow A. Absent or B. <1/3 biopsy area without both marked splenomegaly and leukoerythroblastic reaction No cytogenetic or morphologic evidence for a myelodysplastic syndrome No cause for reactive thrombocytosis

Adapted from Murphy et al.29 *If these measurements suggest iron deficiency, polycythemia vera cannot be excluded unless a trial of iron therapy fails to increase the red blood cell mass into the polycythemic range.

with a recent systematic survey of the disease prevalence in Vicenza, Italy.38 Platelet count was determined in 10,000 consecutive persons, aged 18 to 65 years, and repeated in 99 subjects with values above 400 ⫻ 109/L. Eight persons with confirmed thrombocytosis were carefully investigated for diagnosis of ET and followed for 5 years. Complete evaluation of this cohort of healthy people led to the identification of four cases of ET with an estimated prevalence of 400 cases per million inhabitants (95% confidence interval [CI], 109 to 1.020/million). Interestingly, no thrombotic or hemorrhagic complications occurred over 5 years of follow-up in these incidentally discovered ET patients.

Incidence and Type of Major Thrombotic and Hemorrhagic Complications Thrombosis and hemorrhage are the most frequent clinical complications observed in ET patients.39 In uncontrolled studies, reported cumulative rates for thrombosis and hemorrhage during follow-up ranged from 7% to 17% and 8% to 14%, respectively.40 In one study that also evaluated a control population,41 the incidence of thrombotic episodes was 6.6%

per patient-year in ET versus 1.2% in control subjects, and the rate of major hemorrhagic complications was 0.33% per patient-year in ET versus 0% in controls. The most frequent types of major thrombosis include stroke, transient ischemic attack, myocardial infarction, peripheral arterial thrombosis, and deep venous thrombosis, often occurring in unusual sites, such as hepatic (Budd-Chiari syndrome), portal, and mesenteric veins. In addition to large vessel occlusions, ET patients may suffer from microcirculatory symptoms, including vascular headaches, dizziness, visual disturbances, distal paresthesia, and acrocyanosis. The most characteristic of these disturbances is erythromelalgia, consisting of congestion, redness, and burning pain to ischemia and gangrene of distal portions of the toes and fingers.42 The most frequent bleeding events are hemorrhages from the gastrointestinal tract followed by hematuria and other mucocutaneous hemorrhages. Hemarthrosis and large muscle hematomas are uncommon.

Risk Factors Age over 60 years and a previous thrombotic event were identified as major risk factors for thrombosis in a controlled

Table 2 WHO Diagnostic Criteria for Essential Thrombocythemia Positive criteria 1. Sustained platelet count >600 ⴛ 109/L 2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased number of enlarged, mature megakaryocytes Criteria of exclusion 1. No evidence of PV Normal red cell mass or hemoglobin <18.5 g/dL in men, 16.5 g/dL in women Stainable iron in bone marrow, normal serum ferritin or normal mean corpuscular volume If the former condition is not met, failure of iron trial to increase red cell mass or hemoglobin levels to polycythemia vera range 2. No evidence of chronic myelogenous leukemia No Philadelphia chromosome and no BCR/ABL fusion gene 3. No evidence of myelodysplastic syndrome No del(5q), t(3;3)(q21;q26), inv(3)(q21q26) No significant granulocytic dysplasia, few if any micromegakaryocytes 4. No evidence that thrombocytosis is reactive due to: Underlying inflammation or infection Underlying neoplasm Prior splenectomy Adapted from Imbert et al.30

Essential thrombocytopenia study41 and in uncontrolled series of patients.43,44 Additional risk factors have been also recognized40: biologic characteristics of ET, presence of blood markers of hypercoagulability, and concomitant presence of cardiovascular risk factors. In particular, clonal disease, impaired expression of c-Mpl in bone marrow megakaryocytes, overexpression of PRV-1, presence of factor V Leiden, and antiphospholipid antibodies were associated with a higher incidence of vascular complications. The risk is increased by the concomitant presence of hypertension, hypercholesterolemia, and smoking, but these associations are not consistently found in all studies. Paradoxically, a very high platelet count (⬎1,500 ⫻ 109/L) was found to be a major predictor of bleeding rather than thrombosis.45 The explanation of this comes from the welldocumented impairment of von Willebrand factor (vWF) multimers found both in patients with ET and those with reactive thrombocytosis. Large vWF multimers were decreased in parallel with the degree of thrombocythemia. Moreover, normalization of the platelet count was accompanied by restoration of a normal plasma VWF multimeric distribution and correction of bleeding tendency.

Progression of the Disease ET may transform to MMM or AL as part of the natural history. In a series of 195 patients followed for a median of 7.2 years (range, 1.9 to 24), conversion to MMM was observed in 13 cases, with an actuarial probability of 2.7% at 5 years, 8.3% at 10 years, and 15.3% at 15 years.46 Progression of ET to AL and other hematologic malignancies has been reported sporadically, although the incidence appears less than in the related MPDs.47 In retrospective studies with median follow-up times of 3 to 7 years, leukemic conversion rates ranged from 0.6% to 5%, but most patients had already received cytoreductive therapy.48

Risk-Adapted Therapy Before deciding whether to start platelet-lowering treatment, ET patients should be evaluated for history of thrombotic or hemorrhagic events and the presence of cardiovascular risk factors (smoking, hypertension, hypercholesterolemia, and diabetes). Then, they should be stratified according to their probability of developing major bleeding or thrombosis (see Table 3): these treatment recommendations are based on this risk classification.

Low Risk Avoiding cytoreduction is an option for low-risk ET patients. The natural history of untreated ET was prospectively evaluated in a controlled study that compared 65 low-risk patients with 65 age- and sex-matched normal controls.49 Patients were monitored and cytoreductive therapy was introduced as soon as a major clinical event was recorded. After a median follow-up of 4.1 years, the incidence of thrombosis was not significantly higher in patients than in controls (1.91% v 1.5% per patient-year; age- and sex-adjusted risk ratio, 1.43; 95% CI, 0.37 to 5.4). No major bleeding was observed. These

233 Table 3 Classification of Essential Thrombocythemia Based on Thrombotic and Hemorrhagic Risk Low-risk



Age < 60 years, and No history of thrombosis, and Platelet count < 1,500 ⴛ 109/L Age 40–60 years, and Cardiac risk factors or familial thrombophilia, and Platelet count < 1,500 ⴛ 109/L Age > 60 years, or A previous history of thrombosis or major bleeding, or Platelet count > 1,500 ⴛ 109/L

Correction of cardiovascular risk factors (smoking, hypertension, hypercholesterolemia, diabetes) is recommended in all patients; their contribution to thrombotic risk classification is controversial (see text).

findings were confirmed in a cohort of 74 young women untreated for more than 9 years who had a 1.2% per patientyear incidence of vascular events.43 Thrombotic deaths are rare in low-risk ET subjects, and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1,500 ⫻ 109/L and with no additional risk factors for thrombosis. This policy is based on the low risk of complications and the potential leukemogenicity of cytotoxic drugs. However, the strength of these recommendations is based on studies having small number of patients, and further data from large clinical trials are needed. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia), platelet-lowering agents may be considered. Aspirin at different doses (30 to 500 mg/d) has been found to control microvascular symptoms, such as erythromelalgia, and transient neurologic and ocular disturbances (TIAs), including dysarthria, hemiparesis, scintillating scotomas, amaurosis fugax, migraine, and seizures.42 The efficacy and safety of aspirin, 100 mg daily, in preventing major thrombotic events has been formally assessed in a double-blind, placebo-controlled, randomized clinical trial in PV (European Collaboration on Low-dose Aspirin in Polycythemia [ECLAP] study).50 Aspirin significantly lowered the risk of a primary combined end point including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and major venous thromboembolism (relative risk, 0.4 [95% CI, 0.18 to 0.91], P ⫽ .0277) without increasing major bleeding (relative risk, 1.6 [95% CI, 0.27 to 9.71]). Based on these findings, an antithrombotic preventive strategy with low-dose aspirin is recommended in all PV patients. Translating evidence from this study to ET can be considered, but formal clinical trials have not been performed. The low-risk arm of PT1 (see “Clinical Trials” below) is an observational study addressing this issue in ET.

Intermediate Risk Whether some patients may be classified as at “intermediate risk” of thrombosis is more contentious. The rationale for


G. Finazzi and C. Harrison

assigning this risk category is the increase in incidence of thrombotic events in the age range 40 to 60 years compared to less than 40 years41 and the uncertainty over the weighting that might be ascribed to weaker or more controversial risk factors. The Italian Consensus Criteria define “intermediate risk” as age 40 to 60 years, platelet count less than 1,000 ⫻ 109/L, and either vascular risk factors or familial thrombophilia with no consensus on treatment.40 In a recent review, Elliott and Tefferi suggested that patients aged less than 60 years with no thrombosis and either platelet count greater than 1,500 ⫻ 109/L or cardiovascular risk factor (smoking, diabetes) are of intermediate risk and should be treated with aspirin but concluded there was no consensus on cytoreductive therapy.39 Finally, in the United Kingdom, it is suggested that intermediate-risk patients are aged 40 to 60 years with all of the following: platelet count less than 1,500 ⫻ 109/L, no prior thrombosis or hemorrhage, and no hypertension or diabetes. These patients should be treated with aspirin and they are being entered into an ongoing randomized study comparing hydroxyurea (HU) or no cytoreductive therapy.51

myelodysplastic disorders (MDS) after treatment with HU.52 However, in vivo exposure to HU was not associated with any increase in the number of DNA mutations.58 Many studies have examined the association between multiple myelosuppressive therapies and the occurrence of AL/MDS in ET. In a long-term study of 112 patients, we observed that among 20 patients never treated with chemotherapy, none developed neoplasia, as compared with three of 77 given HU only (3.9%, P ⫽ not significant) and five of 15 given busulfan plus HU (33%, P ⬍.0001).56 Sterkers et al reported 14% of leukemia when HU was combined with other cytotoxic agents, generally pipobroman.52 Six cases of acute myeloid leukemia (AML) (21%) in 28 ET patients treated with HU plus alkylating agents or 32P were observed by Murphy et al.57 In the risk/benefit assessment, HU remains the first-choice drug for most ET patients requiring cytoreductive therapy due to its efficacy in reducing thrombotic complications in randomized clinical trials (see below). Nevertheless, ongoing concerns regarding the risk of leukemia prompted clinicians to test alternative, nonleukemogenic drugs.

High Risk

Anagrelide Anagrelide, an imidazo quinazinoline derivative, reduces the platelet count in a species-specific manner.59 The mechanism by which anagrelide induces thrombocytopenia is unclear but current attention is focused on the TPO/c-Mpl interaction. At high doses, anagrelide also inhibits platelet aggregation by inhibition of phosphodiesterase III; its major side effects are consistent with this effect. These side effects include palpitations, headaches, noncardiac edema, and congestive cardiac failure. In one report, patients treated with anagrelide developed cardiomyopathy.60 There is extensive experience of the use of this drug, which is licensed by the US Food and Drug Administration as a first-line agent for control of thrombocytosis associated with any MPD. In Europe, the drug has been granted a license only for ET patients who are refractory or intolerant of first-line therapy. Until recently, studies of anagrelide in ET were nonrandomized, lacked a control arm, and had relatively limited follow-up. This is especially relevant to ET, as it is frequently an indolent condition associated with prolonged survival.59,61 The largest study to date evaluated 934 ET patients for efficacy and 2,251 for safety61,62 and had a maximum follow-up of 7 years; there was no evidence that anagrelide increased conversion to AL and no mention was made of myelofibrosis. These studies focused primarily on control of platelet count as a surrogate marker of efficacy, but they also reported a decline in concurrent diseaserelated complications. A study of 35 consecutive young ET patients treated with anagrelide, with a median follow-up of 10.7 years, demonstrated that 20% had thrombotic and a similar proportion major hemorrhagic complications, raising a question about the efficacy of anagrelide.63 These events occurred when the platelet count was above 400 ⫻ 109/L, suggesting that control of the platelet count to lower levels might reduce this risk. A second major finding was the development of a significant anemia of more than 3 g/dL in a quarter of patients.

Cytoreduction is recommended in all ET patients at high risk of thrombosis (Table 3). Myelosuppressive therapy (HU), as well as anagrelide and interferon-alpha (IFN-␣) are reasonable options. However, only HU and anagrelide have been evaluated in prospective randomized clinical trials.

Therapeutic Options Hydroxyurea HU has emerged as the treatment of choice in high-risk patients with ET because of its efficacy in preventing thrombosis (see “Clinical Trials” below) and rare acute toxicity. Hematopoietic impairment, leading to neutropenia and macrocytic anemia, is the main short-term toxic effect of HU. Other less frequent side effects include oral and leg ulcers and skin lesions. The leukemogenicity of this agent is still debated. Some long-term studies found that a proportion of ET patients treated with HU developed AL.52 In other studies, however, this drug was rarely associated with secondary malignancies. In a recent analysis of 25 ET patients younger than 50 years and treated with HU alone for a high risk of thrombosis, no leukemic or neoplastic transformation occurred after a median follow-up of 8 years (range, 5 to 14).53 In 1,638 patients with PV prospectively enrolled in the ECLAP study, HU alone did not enhance the risk of leukemia in comparison with patients treated with phlebotomy only (hazards ratio, 0.86; 95% CI, 0.26 to 2.88; P ⫽ .8), whereas this risk was significantly increased by previous therapies with radiophosphorus, busulfan, or pipobroman (hazards ratio, 5.46; 95% CI, 1.84 to 16.25; P ⫽ .002), although the median follow-up of these patients is short.54 The incidence of acute leukemic transformation is higher in patients with ET who have cytogenetic abnormalities55 and in those receiving multiple cytotoxic drugs with different mechanisms of action.52,56,57 The 17p deletion has been described in a proportion of ET patients who developed AL and

Essential thrombocytopenia Interferon-alpha IFN-␣ has been evaluated in several cohorts of ET patients.64 Platelet count was reduced to less than 600 ⫻ 109/L in approximately 90% of cases after about 3 months, with an average dose of 3 million international units (IU) daily. The time and degree of platelet reduction during the induction phase were dose-dependent. The IFN-␣ dose can be tapered during maintenance, but after its discontinuation the platelet count rebounds in the majority of patients. IFN-␣ is not known to be teratogenic and does not cross the placenta. Thus, it has been used successfully throughout pregnancy in some ET patients with no adverse fetal or maternal effects. Side effects are a major problem with this drug. In a series of 273 ET patients,64 IFN-␣ therapy was terminated in 25% (67 cases) before completion of the treatment. The rate of withdrawal ranged between 0% and 66% in the different studies. This wide range may be partly explained by the difference in observation times that ranged from 1 month to 4 years. The most common reasons for withdrawal were drugrelated side effects, seen in 55%, and patient refusal in 10%. So far, no leukemogenic effects have been reported. However, in a retrospective analysis of more than 2,000 ET patients from the Italian registry, 159 were given only IFN-␣ and two developed leukemia. Despite its high cost and toxicity, IFN remains a promising agent in cytoreductive treatment of ET, especially in pregnant women.

Clinical Trials Two randomized clinical trials have assessed benefits and risks of myelosuppressive therapy in ET patients at high risk of thrombosis. The first was performed about 10 years ago in Italy and evaluated HU versus untreated controls65: 114 ET patients (35 men and 79 women; median age, 68 years [range, 40 to 85]; median platelet count, 788 ⫻ 109/L [range, 533 to 1,240,000/␮L]) were randomized to HU (n ⫽ 56) or no cytoreductive treatment (n ⫽ 58). During a median follow-up of 27 months, two thromboses (one stroke and one myocardial infarction) were recorded in the HU-treated group (1.6% per patient-year) compared with 14 in the control group (one stroke, five TIAs, five peripheral arterial occlusions, one deep vein thrombosis, and two patients with superficial thrombophlebitis) (10.7% per patient-year; P ⫽ .003). This study provided the basis for considering HU as the standard therapy for high-risk ET patients and the reference arm for other randomized trials. The second trial, named Primary Thrombocythaemia 1 (PT1), has three arms based on thrombotic risk.66. The lowrisk aspirin only (observation) and intermediate-risk (randomization between aspirin v aspirin and HU) arms of this study continue to recruit patients (information available at The high-risk arm compared aspirin and anagrelide with aspirin and HU for patients with any one of the following risk factors: age greater than 60 years, prior thrombosis or hemorrhage, platelet count greater than 1,000 ⫻ 109/L, and/or either hypertension or diabetes requiring therapy. In total, 809 high-risk patients were analyzed with a median follow-up of 39 months.

235 Overall, patients randomized to anagrelide and aspirin were more likely to reach the composite primary end point of major thrombosis (arterial or venous), major hemorrhage, or death from a vascular cause (P ⫽ .03). When individual end points were assessed, arterial thrombosis, major hemorrhage, and myelofibrosis were all significantly more frequent for patients treated with anagrelide (P ⫽ .004, .008, and .01, respectively). Of all categories of arterial thrombosis, the difference was only significant for transient ischemic attacks (14 v 1), but each was more common in anagrelide-treated patients. However, anagrelide and aspirin seemed to offer at least partial protection from thrombosis, as the prevalence of thrombotic events (8%) was significantly lower than the control arm of the previous study (28%),65 while the HU arms were approximately equivalent. The success of HU is likely to reflect the importance of additional factors such as hematocrit, leukocytes, or neutrophil count, or subtle effects on the endothelium in the pathogenesis of thrombosis. However, venous thrombosis was less frequent in patients treated with anagrelide (P ⫽ .006). Major hemorrhage, defined as bleeding in a critical site (such as intracranial), requirement for blood transfusion, or decrease in hemoglobin by more than 2 g/dL, was increased for anagrelide treatment (P ⫽ .008). The most frequent of these end points was gastrointestinal hemorrhage. Hemorrhagic events may result from some subtle effect on platelet function, possibly accentuated by aspirin or in relation to combined gastric toxicity. It has been suggested that anagrelide at therapeutic doses has minimal effects on platelet function,67 but it has been suggested that although anagrelide reduces the platelet count it does not reverse platelet dysfunction.68 Myelofibrotic transformation was seen in 16 patients treated with anagrelide in comparison to five treated with HU. In the large noncontrolled cohorts of patients treated with anagrelide, myelofibrosis was a late complication and the median follow-up in these studies was relatively short for a chronic disease such as ET.61,63,69-71 It seems logical to conclude that anagrelide might be less effective than HU at suppressing the natural evolution of ET to myelofibrosis as the number of megakaryocytes remains elevated in ET patients treated with anagrelide compared to those given HU. There is also evidence that despite control of the platelet count, levels of transforming growth factor-beta remain elevated in patients treated with anagrelide.72,73 The incidence of myelofibrosis in the anagrelide arm (3.95%) at a median follow-up of 39 months is approximately in accordance with what has previously been reported (0.9% per annum),46 supporting the view that HU may be more effectively suppressing myelofibrosis. It is important to emphasize that these myelofibrotic transformations were clinical end points reported by the local investigator. The diagnostic criteria in the trial included severe fibrosis on trephine biopsy and clinical factors such as progressive splenomegaly, unexplained anemia, constitutional symptoms, and characteristic blood film changes. Statistical subanalysis excluded excessive weighting from any of these clinical criteria. Furthermore, while it is likely that some of the PT1 patients would currently be classed as pre-

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236 fibrotic or early myelofibrosis, the randomization and significant size of the trial mitigate against this being a confounding factor. A comprehensive evaluation of histologic and other biologic variables for the high-risk group of patients is currently underway.

Pregnancy ET is unique among the other Ph-negative MPDs in that it is relatively common among women of child-bearing age.74 More than 280 pregnancies in ET patients have been reported in retrospective case series. Yet there are conflicting data on predicting pregnancy outcome and the optimal management strategy of ET pregnancies. The live birth rate has been 50% to 57%, first trimester loss has occurred in 26% to 36%, and late pregnancy loss has been seen in 5% to 9.6% pregnancies, while intra-uterine growth retardation (IUGR) occurred in 4% to 5.1%, preterm delivery in 5.6% to 8%, and placental abruption in 2.8% of ET pregnancies.75,76 Maternal complications are relatively rare with no fatalities, but major thromboses including sagittal sinus thrombosis, deep vein thrombosis, and transient ischemic attacks have been reported.77 Many of these events occurred in the postpartum period, emphasizing the need for postpartum thrombo-prophylaxis. Three major bleeding events were reported78: none of these patients was treated with aspirin but all had acquired von Willebrand’s disease. The apparent low risk of maternal complications must be considered in context, as the majority of these patients have “low-risk” ET. Most pregnant ET patients not in the high-risk category should probably be treated with aspirin and postpartum prophylaxis with heparin and closely monitored for complications. For those patients with previous pregnancy or disease-related complications (more than three first trimester or one second or third trimester loss, severe IUGR, preeclampsia, significant hemorrhage or thrombotic event, and/or extreme thrombocytosis) therapeutic options include aspirin, low molecular weight heparin, and IFN-␣. Some investigators have suggested that for ET patients with prior pregnancy complications IFN-␣ might improve the outcome in subsequent pregnancies79,80; a recent review suggested a similar benefit.77 This is contentious as it is based on an uncontrolled retrospective analysis of 25 patients in whom IFN-␣ treatment was reported and only continued through pregnancy in 20 cases. Other uncertain areas include the selection of a threshold for extreme thrombocytosis, and whether prior pregnancy complications predict likely outcome of future pregnancies. The answers to key questions are still lacking and there is a need for international collaboration to address these issues and define best care.

Conclusions Consensus-based practice guidelines for the therapy of ET have been developed recently in Italy.40 Convincing evidence is emerging that the treatment of ET patients should be based primarily on the expected risk of major thrombotic complications. Although the specific values chosen for separating

Figure 1 An algorithm of treatment recommendations in patients with essential thrombocythemia (ET). Classification of intermediate risk is controversial: a randomized study comparing aspirin versus aspirin plus HU in intermediate-risk patients is ongoing (see text)

different risk categories are partly arbitrary, some recommendations can be made (Fig 1). Young asymptomatic subjects with platelet counts below 1,500 ⫻ 109/L are at lower risk and can be followed untreated. The prophylactic use of aspirin is optional and should be considered on an individual basis. Any concomitant cardiovascular risk factors should be appropriately managed. More contentious is whether patients with “soft” risk factors should be classified as intermediate risk and, if so, how to manage them: the PT1 trial has an ongoing randomization assessing this. For high-risk patients, HU plus aspirin is the treatment of choice because its efficacy in preventing thrombotic complications was demonstrated in randomized clinical trials. Anagrelide and IFN-␣ should be considered as “second-line” therapies in patients refractory to HU; IFN-␣ may have a role particularly in pregnant women. Future challenges are to advance our understanding of the molecular pathogenesis of ET and to use these discoveries therapeutically.

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